1. Field of the Invention
The invention relates generally to enhancing the immunogenicity and therefore the treatment of disease conditions with vaccines and more specifically to the utilization of a cationic liposome DNA complex (CLDC) to bolster the immunogenic capabilities of vaccines.
2. Background Information
In the early 1990's a gene delivery system was being developed that employed the use of liposomes complexed to plasmid DNA (coding) with the goal of eliciting expression of the delivered gene product in target tissues. Early on it was recognized that the injection of the complex of plasmid DNA and liposomes resulted in a profound activation of innate host immunity. This immune activation occurred whether or not the plasmid component was a coding vector or non-coding ‘empty’ vector. This effect was also significantly dependent upon formation of the complex of plasmid and cationic lipids, since neither entity alone had significant stimulatory properties except at exceedingly high in vivo doses. Since these early observations, it has become recognized that the stimulation of innate immunity triggered by cationic lipid-DNA complexes (CLDC) was due in part to a liposome-mediated potentiation of the inherent responsiveness of the mammal, fish or bird immune system to non-methylated CpG motifs within the bacterial DNA of the plasmids. Recently it has been recognized that CpG motifs function via interaction with the Toll-like receptor 9 (TLR-9) an interaction that requires internalization—an event that is facilitated significantly by the lipid component. Liposomes have been shown to enhance the immunostimulatory activity of CpG oligonucleotides (ODN) by 15-40 fold. The degree of immunostimulation by CLDC was so profound and predictable that it became known in the gene therapy field as the ‘empty-vector’ effect. This route-sensitive and dose-dependent effect has been recognized in multiple species and is characterized by almost immediate up-regulation of a broad-array of host soluble and cellular defenses. In addition to up-regulation of innate immunity, the immune stimulatory effect serves as a potent adjuvant for microbial and ‘cancer’ antigen-based vaccines.
Hyporesponsiveness to excessive innate immune stimulation has been studied extensively in vitro and documented in clinical treatment of sepsis patients. Characterization of the cells from these hyporesponsive patients indicated low inflammatory cytokine production in response to stimulus, reduced expression for HLA-DR, and generally a reduced capability for antigen presentation. This hyporesponsive state has also been demonstrated in vitro using human cells using lipopolysaccharide and lipoteichoic acid and recently in murine RAW264.7 cells using CpG oligonucleotides.
There is a continued need to provide better vaccines which can produce an immune response which is safe, antigen-specific and effective to prevent and/or treat diseases amenable to treatment by elicitation of an immune response, such as infectious disease, allergy and cancer.
The present invention assists the development of vaccines and vaccine strategies where a high level of protective titers are necessary following a single or a multiple vaccination or a combination of innate and adaptive immune response and protection is desired.